This invention relates to new compounds useful, inter alia, as intermediates for preparation of pharmacologically useful compounds.
Small, highly substituted hydrophilic amines are frequently employed industrially, for example as aids in the textile, leather, and papers industries, as raw materials for detergents, as solubilizing substituents in pharmaceuticals, etc. Of maximum importance is their use in the synthesis of X-ray contrast media. In this case, a basic molecular substrate, highly substituted with iodine atoms for the purpose of X-ray absorption, is further substituted with hydrophilic residues to ensure water solubility and physiological compatibility. These substituents, by their structure, have a decisive influence on these properties of the X-ray contrast media.
The synthesis of novel X-ray contrast media thus is frequently dependent on the availability of new, suitable intermediates which when combined as substituents impart to the basic component the desired characteristics. Since most X-ray diagnostic techniques require the use of relatively large amounts of contrast medium, it is also necessary to manufacture the X-ray contrast medium and its requisite intermediates conveniently and economically.
It is especially advantageous to effect the linkage between the iodine-containing basic component and the hydrophilic substituent by way of an amide bond. This bond is stable and, due to its polarity, likewise contributes toward rendering the entire molecular water-soluble.
Many examples of this type of compound can be found in the literature. Also, this acyl function is included in multiple form. Thus, Belgian Pat. No. 836,355 (or U.S. Pat. No. 4,001,323) discloses the synthesis of 5-(.alpha.-hydroxypropionylamino)-2,4,6-triiodoisophthalic acid N,N'-bis(1,3-dihydroxyprop-2-yl)diamide(iopamidol), while the synthesis of metrizamide[2-(3-acetamido-5-N-methylacetamido-2,4,6-triiodobenzamido)-2-d eoxy-D-glucose] is described in DOS No. 2,031,724 (or U.S. Pat. No. 3,701,771). Both compounds have been introduced commercially.
European Application No. 0,033,426 discloses 5-acetamido-2,4,6-triiodoisophthalic acid N,N'-bis(1,3,4-trihydroxybut-2-yl)diamide, as well as 2,4,6-triiodotrimesic acid N,N',N"-tris(1,3,4-trihydroxybut-2-yl)triamide, both of which contain 2-amino-1,3,4-butanetriol as the amine component.
In the reactions described therein, iodinated basic components are utilized. These carry one or several acid chloride groups. The latter are reacted with an alkylamine substituted by hydroxy groups.
The high hydrophilicity desired in the final product X-ray contrast medium proves, however, to be a disadvantage in the preparation of these compounds. Such compounds are hard to purify due to their low tendency toward crystallization as well as their poor solubility in aprotic, low-boiling solvents.
The purity of the final products and thus also the cost of the ultimate purification is decisively affected by the reaction speed with which the acid chloride and the amine react. The speed is higher in the case of an aminomethyl group --CH.sub.2 --NH.sub.2 than for a sterically hindered amine. For this reason, those amines are found to be most suitable for the synthesis of X-ray contrast media wherein the amino group is not sterically hindered, and the hydroxy groups are entirely or partially blocked.
For example, aminotrihydroxybutane exists as four isomeric compounds: ##STR2## When using it as the hydroxylated alkylamine in the synthesis, compound Va will be most advantageous for reaction with an acid chloride since the amino group is least hindered sterically. However, since its primary hydroxy group can likewise react with the acid chloride and can lead to secondary products, it is expedient to utilize compound Va as an intermediate I wherein the hydroxy groups are blocked.
Similar amines are also used in European Patent Application No. 0,033,426; such as, for example, compounds of Formula (VI) ##STR3## However, these compounds have the crucial disadvantage that they contain a sterically hindered amino group ##STR4## requiring more drastic reaction conditions than an aminomethylene group --CH.sub.2 --NH.sub.2. They lead to by-products, making the purification of the final products problematic. Additionally, since the compounds of Formula (VI) are dioxepanes, they represent a sterically stressed 7-membered ring system which, as experience has shown, is less stable with respect to a weakly acidic medium than a 5-membered ring system. By premature cleavage of blocking groups, these compounds increase the danger of the occurrence of by-products.